Lupus glomerulonephritis (GN) and its ensuing renal insufficiency is a key feature of systemic lupus erythematosus (SLE) and one of the major prognostic factors. In lupus GN, immune complex deposition occurring predominantly in the glomerulus is accompanied by varying degrees of interstitial and tubular inflammation, atrophy and fibrosis. Tubular atrophy has been shown to be highly predictive of renal failure outcome in diffuse proliferative lupus nephritis and other glomerular diseases. Current evidence suggests that apoptosis is one of the pathogenetic mechanisms of tubular atrophy. Tumor necrosis factor apoptosis inducing ligand (TRAIL), a member of the TNF family, induces apoptosis in multiple cell types but also exerts mitogenic, immunoregulatory or proinflammatory functions. In our previous studies we have demonstrated the increased expression and apoptotic ability of membrane and sTRAIL from T cells in lupus patients with active disease. Our preliminary data demonstrate increased expression of TRAIL and its death signaling receptors DR4 and DR5 in proximal and distal tubules in kidney biopsies from patients with lupus nephritis compared to non-SLE renal diseases. Our data also indicate that in vitro, expression of TRAIL, DR4 and DR5 is modulated by TNF- alpha and IFN-gamma, key cytokines in the development of lupus GN. Paradoxically, TRAIL does not induce apoptosis of human proximal tubular epithelial cells (PTEC), but rather exerts a mitogenic effect. In this proposal we will test the hypothesis that TRAIL exerts a nonapoptotic, mitogenic function on human PTEC and characterize the molecular mechanisms by which TRAIL mediated signals may be involved in this function. In specific aim #1 we will characterize the contribution of DR4 and DR5 to TRAIL induced PTEC proliferation. Specific aim #2 will focus on the intracellular mechanisms engaged in TRAIL-induced proliferation of PTEC, specifically those involving NF-kB, the MAP kinases p38, ERK1, JNK and PI3 kinase/Akt. Finally, in specific aim #3 we will determine the in vivo relevance of TRAIL induced PTEC proliferation and assess the proliferation index of tubular cells expressing TRAIL, DR4 and DR5 in situ in lupus GN compared to cells that that do not express them in non-SLE renal diseases. The proposed research has a high relevance to our understanding of the role of TRAIL/TRAIL receptor interaction in lupus nephritis pathogenesis.